Submissions for variant NM_002907.4(RECQL):c.1426G>A (p.Asp476Asn)

gnomAD frequency: 0.00003  dbSNP: rs200259739

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346257	SCV001540441	uncertain significance	not provided	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 476 of the RECQL protein (p.Asp476Asn). This variant is present in population databases (rs200259739, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 27125668). ClinVar contains an entry for this variant (Variation ID: 1042323). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RECQL protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001346257	SCV001796900	uncertain significance	not provided	2024-08-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); Observed in individuals with breast cancer, but also in unaffected controls (PMID: 27125668, 32546565); This variant is associated with the following publications: (PMID: 32546565, 27125668, 27248010, 19151156, 23396353)
Ambry Genetics	RCV004036487	SCV002698439	likely benign	not specified	2020-07-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001346257	SCV003799566	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	The RECQL c.1426G>A; p.Asp476Asn variant (rs200259739), is reported in the literature in an individual affected with breast cancer, but without clear disease association (Kwong 2016), and is also found in a healthy control (Song 2021). This variant is reported in ClinVar (Variation ID: 1042323) and is found in the general population with an overall allele frequency of 0.0036% (9/250,448 alleles) in the Genome Aggregation Database. The aspartate at codon 476 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.686). Due to limited information, the clinical significance of the p.Asp476Asn variant is uncertain at this time. References: Kwong A et al. Germline RECQL mutations in high risk Chinese breast cancer patients. Breast Cancer Res Treat. 2016 Jun;157(2):211-215. PMID: 27125668. Song H et al. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. J Med Genet. 2021 May;58(5):305-313. PMID: 32546565.